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Flunitrazepam (IPA: /ˌfluːnaɪˈtræzəpæm/; is marketed by Roche under the trade name Rohypnol. It is a powerful hypnotic drug that is a short-intermediate acting benzodiazepine derivative. It has powerful hypnotic, sedative, anxiolytic, and skeletal muscle relaxant properties.
Flunitrazepam is commonly prescribed for the treatment of insomnia. Just as with other hypnotics, flunitrazepam should only be used on a short term basis or in those with chronic insomnia on an occasional basis.
The drug is sometimes used as a date rape drug (commonly referred to in street slang as a "roofie").
Flunitrazepam is classed as a nitrobenzodiazepine. Other nitrobenzodiazepines include nitrazepam and clonazepam.
Additional recommended knowledge
While 80% of flunitrazepam that is taken orally is absorbed, bioavailability in suppository form is closer to 50%.
Benzodiazepines such as flunitrazepam are lipophilic and rapidly penetrate membranes.
Flunitrazepam has a long half-life of 18 - 26 hours and an active metabolite which has a half life of 36-200 hours, which means flunitrazepam effects after nighttime administration persist throughout the next day. Residual 'hangover' effects after nighttime administration of flunitrazepam such as sleepiness, impaired psychomotor and cognitive may persist into the next day which may impair the ability of users to drive safely and increase risks of falls and hip fractures.
Flunitrazepam is lipophilic and is metabolised hepatically via oxidative pathways. The enzyme CYP3A4 is the main enzyme in its phase 1 metabolism.
Benzodiazepines, including flunitrazepam, bind to glial cell membranes with high affinity. Flunitrazepam has an inhibitory effect on plasma cholinesterase of 60--90 per cent.
The main pharmacological effects of flunitrazepam are the enhancement of GABA at the GABAA receptor. Like other benzodiazepines, flunitrazepam's pharmacological effects include sedation, muscle relaxation, reduction in anxiety, and prevention of convulsions.
Flunitrazepam's effects are approximately 7 to 10 times more potent than diazepam. The effects of flunitrazepam appear approximately 15 to 20 minutes after oral administration, and last for approximately four to six hours. Some residual effects can persist up to 12 hours or more after administration.
Adverse effects of flunitrazepam include dependence, both physical and psychological, reduced sleep quality resulting in somnolence and overdose, resulting in excessive sedation, impairment of balance and speech, respiratory depression or coma and possibly death. Because of the latter, flunitrazepam is commonly used in suicide. When used in pregnancy, it might cause floppy infant syndrome. Other adverse effects include cognitive and motor dysfunctions.
Flunitrazepam is considered to be one of the most addictive of the benzodiazepines, along with clonazepam, lorazepam, alprazolam, and particularily, temazepam, nitrazepam, and nimetazepam. Its use causes several notable side effects, including:
Flunitrazepam is a preferred benzodiazepine in addicts with massive drug usage. Long-term use of flunitrazepam can result in psychological and physical dependence.
Discontinuation may result in the appearance of withdrawal symptoms when the drug is discontinued. Abrupt withdrawal may lead to a severe benzodiazepine withdrawal syndrome characterised by seizures, psychosis, severe insomnia and severe anxiety. Rebound insomnia, worse than baseline insomnia, typically occur after discontinuation of flunitrazepam even after short term single nightly dose therapy.
Regular use of flunitrazepam may lead to a hypnotic drug dependence.
Flunitrazepam produces a decrease in delta wave activity. The effect of benzodiazepine drugs on delta waves, however, may not be mediated via benzodiazepine receptors. Delta activity is an indicator of depth of sleep within non-REM sleep; increased levels of delta sleep reflects poorer quality of sleep. Thus flunitrazepam and other benzodiazepines cause a deterioration in sleep quality. Cyproheptadine may be superior to benzodiazepines in the treatment of insomnia as it enhances sleep quality based on EEG studies. This may lead to somnolence.
Flunitrazepam is a drug which is very frequently involved in drug intoxication, including overdose. Overdose of flunitrazepam may result in excessive sedation, impairment of balance and speech. This may progress in severe overdoses to respiratory depression or coma and possibly death. The risk of overdose is increased if flunitrazepam is taken in combination with alcohol, opiates or other CNS depressants.
This lethal effect of flunitrazepam overdose is commonly used in suicide, as seen in Abuse potential section.
Flunitrazepam overdose responds to the benzodiazepine receptor antagonist flumazenil, which thus can be used as a treatment.
Floppy infant syndrome
Benzodiazepines such as flunitrazepam are lipophilic and rapidly penetrate membranes and therefore rapidly crosses over into the placenta with significant uptake of the drug. Use of benzodiazepines including flunitrazepam in late pregnancy, especially high doses, may result in floppy infant syndrome.
After disconinuation of flunitrazepam a rebound effect may occur about 4 days after stopping flunitrazepam. (See benzodiazepine withdrawal syndrome)
Flunitrazepam impairs cognitive functions. This may appear as a lack of concentration, confusion and anterograde amnesia. At can be described as a hangover-like effect, with impairment of mental arithmetic abilities.
Impaired psychomotor functions is another adverse effect, affecting reaction time and driving skill. This may also be expressed as impaired coordination, impaired balance and dizziness.
Other adverse effects include:
The use of flunitrazepam in combination with alcohol synergizes the adverse effects, and can lead to toxicity and death.
Benzodiazepines including flunitrazepam may inhibit the glucuronidation of morphine leading to increased levels of and prolongation of the effects of morphine.
Flunitrazepam and other benzodiazepines may inhibit neurosteroid metabolism, with alterations in the levels of progesterone, which in turn may adversely influence the functions of the brain and reproductive system. The pharmacological actions of neurosteroids are similar to those of benzodiazepines, as they are positive allosteric modulators of the GABAa receptor, enhancing GABA function. Thus, long-term administration of benzodiazepines may influence the concentrations of endogenous neurosteroids, and thereby would modulate the emotional state. Factors which effects benzodiazepines ability to alter neurosteroid levels depend on the molecular make up of the individual benzodiazepine molecule.
Despite the fact that flunitrazepam is a Schedule IV controlled substance, it is not commercially available in the United States. Currently the DEA is recommending that Rohypnol be reclassified to Schedule I.
Drug-facilitated sexual assault
Flunitrazepam is known to induce anterograde amnesia in sufficient doses; individuals are unable to remember certain events that they experienced while under the influence of the drug. This effect is particularly dangerous when flunitrazepam is used to aid in the commission of sexual assault; victims may not be able to clearly recall the assault, the assailant, or the events surrounding the assault.
It is difficult to estimate just how many flunitrazepam-facilitated rapes have occurred in the past. Very often, biological samples are taken from the victim at a time when the effects of the drug have already passed and only residual amounts remain in the body fluids. These residual amounts are difficult, and sometimes impossible, to detect using standard screening assays available in the United States. If flunitrazepam exposure is to be detected at all, urine samples need to be collected within 72 hours and subjected to sensitive analytical tests. The problem is compounded by the onset of amnesia after ingestion of the drug, which causes the victim to be uncertain about the facts surrounding the rape. This uncertainty may lead to critical delays or even reluctance to report the rape and provide appropriate biological samples for testing. If a person suspects that he or she is the victim of a flunitrazepam-facilitated rape, he or she should get laboratory testing for flunitrazepam as soon as possible. In recent news it has been discovered that scientists can now detect flunitrazepam and related compounds in urine at least up to 5 days after administration of a single dose of Rohypnol and up to a month in hair.
It must be noted that an inability to remember events, including sexual encounters, is not conclusive evidence of having consumed a drugged drink: Drunkenness itself causes blackouts, sleepiness, and a reduction in inhibitions. Only a timely screening for flunitrazepam can demonstrate its use. It has been shown that alcohol alone is the substance used in the vast majority of cases of date-rape. A recent study conducted by doctors in the U.K. found that none of the subjects reporting spiked drinks had any traces of flunitrazepam or other medications popularly believed to be associated with rape such as GHB. The study claims that binge drinking was to blame.
In the United Kingdom, the use of flunitrazepam and other "date rape" drugs has been connected to stealing from sedated victims. One expert quoted in a British newspaper estimated that up to 2,000 individuals are robbed each year after being spiked with powerful sedatives, making drug-assisted robbery a more common problem than drug-assisted rape.
Criminals sometimes use flunitrazepam before committing robbery as it has a calming and anti-emotive effect. This allows the criminal to perform the robbery without becoming anxious. Flunitrazepam is also known to induce anterograde amnesia making police interrogations more difficult.
In a notable flunitrazepam related case, Selina Hakki was found guilty in December 2004 of using flunitrazepam to drug wealthy men and rob them of their clothes and accessories in the UK.
Although flunitrazepam has become widely known in USA for its use as a date-rape drug, it is used more frequently as a recreational drug. It is used by high school and college students, rave party attendees, and heroin and cocaine users (who call a dose of flunitrazepam a "roofie") for recreational purposes, including:
Flunitrazepam is usually consumed orally, and is often combined with alcohol. It is also occasionally insufflated (i.e. tablets are crushed into powder and snorted). In some European countries, there was an alcohol solution of flunitrazepam (Darkene), taken by injection, with very strong effects.
Benzodiazepines, including diazepam, nitrazepam, oxazepam and flunitrazepam account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines, suggesting benzodiazepines are a major prescription drug class of abuse. Nitrazepam and flunitrazepam accounted for the vast majority of forged prescriptions.
Flunitrazepam and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other benzodiazepines and zolpidem and zopiclone are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range suggesting a high degree of abuse potential for benzodiazepines and zolpidem and zopiclone.
Benzodiazepines were implicated in 39% of suicides by drug poisoning in Sweden, with nitrazepam, temazepam, and flunitrazepam accounting for 90% of benzodiazepine implicated suicides, in the elderly over a period of 2 decades. In three quarters of cases death was due to drowning, typically in the bath. Benzodiazepines were the predominant drug class used in suicides in this review of Swedish death certificates with 72% of benzodiazepine overdoses showing that benzodiazepines were the sole drug used in deaths by overdose. Benzodiazepines and in particular temazepam, nitrazepam and flunitrazepam should therefore be prescribed with caution in the elderly.It was also found that in about a third of overdose cases involving benzodiazepines, benzodiazepines were the sole cause of death.
In a retrospective study of deaths, when benzodiazepines were implicated in the deaths, the benzodiazepines flunitrazepam, temazepam, and nitrazepam were the most common benzodiazepines involved. Benzodiazepines were a factor in all deaths caused by drug addiction in the study. Nitrazepam, temazepam, and flunitrazepam were significantly more commonly implicated in suicide related deaths than natural deaths. In four of the cases benzodiazepines alone were the only cause of death. It was concluded that flunitrazepam, temazepam, and nitrazepam were significantly more toxic than other benzodiazepines.
Flunitrazepam is currently a Schedule III drug under the international Convention on Psychotropic Substances of 1971; in the United States, it is on Schedule IV
According to FDA Associate Director for Domestic and International Drug Control Nicholas Reuter:
Rohypnol is currently under consideration to be rescheduled to Schedule I, and is already considered such in the States of Florida, Idaho, Minnesota, New Hampshire, New Mexico, North Dakota, Oklahoma, and Pennsylvania.
21 U.S.C. § 841 and 21 U.S.C. § 952 provide for stiff prison terms for the possession of flunitrazepam; penalties for use or distribution include life in prison, should death or serious injury occur.
In Australia, flunitrazepam is a schedule 8 drug, along with amphetamines and narcotic analgesics. All other benzodiazepines (except Temazepam) are schedule 4 drugs. Unauthorized possession of certain quantities of the drug is punishable by criminal sanctions in New South Wales under Schedule 1 of the Drug Misuse and Trafficking Act 1985.
On January 1 2003 flunitrazepam was moved up one level in the schedule of controlled drugs and on August 1st 2004 the manufacturer Roche removed Rohypnol from the market.
Intermediate half life benzodiazepines are also useful for patients with difficulty in maintaining sleep eg loprazolam, lormetazepam, temazepam and may be preferable to long half life benzodiazepines which typically cause next day sedation and impairments.
Street names for Rohypnol include rophy, rufflels, roofies, ruffies, ruff up, rib, roach 2, R2, R2-Do-U, roche, rope, ropies, circles, circes, forget it, forget-me-pill, forget-me-now, Baptist Communion, and Mexican Valium.
Flunitrazepam was first synthesized in the early 1970s by Roche and was used in hospitals when deep sedation was needed. It first entered the commercial market in Europe in 1975, and in the 1980s it began to be available in other countries. It first appeared in the U.S. in the early 1990s. It originally came in 1 mg, 2 mg, and 5 mg doses, but due to its potency and potential for abuse the higher doses were soon taken off the market. It is now only available in 1 mg.
Categories: Anticonvulsants | Anxiolytics | Benzodiazepines | Hoffmann-La Roche | Hypnotics | Muscle relaxants | Sedatives
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Flunitrazepam". A list of authors is available in Wikipedia.|